Drug-induced tissue lesions are nearly always of grave concern to the physician and often lead to organ failure or even death of the patient. These toxic drug reactions are also the greatest impediment to the rapid development of new chemical entities into useful therapeutic agents. Elucidation of their underlying pathogenetic mechanisms has not been possible in the past and attempts to explain them on the basis of the chemical structure of the parent drug has failed, as is readily apparent from a quick comparison of such strikingly different compounds as paraquat and nitrofurantoin which nevertheless appear to share similar pulmonary toxicities. The discovery that many drug-induced tissue lesions are initiated by the formation of chemically reactive metabolites from the drugs has made it possible to begin to classify and arrange the reactions into general groups. We believe that many of the drug-induced tissue lesions might best be understood, categorized, and ultimately predicted on the basis of the nature of the chemically reactive intermediate that is initiating so many of these life-threatening drug injuries. However, an interdisciplinary, highly integrated approach is necessary in order to correlate the formation of chemically reactive metabolites with the incidence, types, and severities of toxicities caused by drugs and other foreign compounds. One needs to correlate the findings of several different kinds of studies including the measurement of biological half-life of the drug, the quantitative isolation of urinary drug metabolites, the determination of the amount of covalent binding of reactive metabolites both in vivo and vitro and measurement of tissue peroxidative reactions. Determination of the effects of various pretreatments concomitantly on these paramenter is essential. Careful consideration of the types of electrophilic and radical metabolites of drugs that might be formed, and their likely chemical reaction mechanisms with tissue molecules, should make it increasingly possible to understand the molecular basis for many drug-induced tissue injuries. An understanding of the biochemical mechanisms of human drug toxicity is requisite for rational risk/benefit decision-making and for any approaches to prevention of toxicity or the development of new non-toxic analogues to replace currently toxic agents.